Signal Mechanisms of M2 Macrophage Activation

Abstract

In the previous chapters, we have reviewed the definition and major functions of M2 macrophages of mammals, the evolutionary origin of the M2 macrophages, and possible M2 macrophage equivalents in invertebrates and nonmammalian vertebrates. This chapter is dedicated to the molecular mechanisms that drive M2 macrophage activation, or as often called, M2 macrophage polarization. There are prototypical M2 activating signals: Th2 cytokines, and the uptake of apoptotic cells. Th2 cytokines act through signal transducer and activator of transcription 6 (STAT6) by inducing its phosphorylation, nuclear translocation, and promoting transcription of STAT6-responsive genes. Apoptotic cells are metabolized within the macrophages, eventually activating lipid-sensing nuclear receptors. Excess M2 macrophage number and unwanted M2 macrophage activation cause disease; hence, mechanisms that inactivate STAT6 signaling are important to balance macrophage activation. Inactivation of STAT6 signaling can occur via STAT6 ubiquitination by the ubiquitin ligase ring finger protein 128 [RNF128, also known as gene related to anergy in lymphocytes (GRAIL)]. Ubiquitination of STAT6 leads to its proteasomal degradation, hence allowing an M2 activation state to be switched off. There are noncanonical inducers of M2 genes, such as certain pathogen products, inflammatory mediators, lipid metabolites, hormones, and neurotransmitters. Epigenetic modifications also affect M2 activation, and there is an autocrine cytokine loop that sustains M2 activation.